Compositions and resulting hard capsules comprising hydrophilic coloring foodstuff concentrates

ABSTRACT

An aqueous composition for making dip-molded comestible hard capsules comprising a film forming capsule base material and one or more colorants each consisting of a hydrophilic coloring foodstuff concentrate.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 16/789,701, filed onFeb. 13, 2020, which is a continuation of U.S. patent application Ser.No. 16/070,499, filed on Jul. 16, 2018, now U.S. Pat. No. 10,603,286,which is the U.S. National Stage of International Application No.PCT/IB2016/058123, filed Dec. 30, 2016, which was published in Englishunder PCT Article 21(2), which in turn claims the benefit of EuropeanPatent Application No. 16153238.7, filed Jan. 28, 2016, and EuropeanPatent Application No. 16153306.2, filed Jan. 29, 2016, which are allincorporated herein in their entireties.

FIELD

The present disclosure relates to compositions and resulting dosage formarticles for the delivery of one or more drugs/medicaments (or healthand nutrition materials) via oral, vaginal, rectal or other,administration of the same to a subject. More particularly, the dosageform articles are comestible and suitable for assimilation by a subject,preferably the subject being selected from humans or animals.

The compositions and resulting capsules comprising one or more colorantseach consisting of hydrophilic coloring foodstuff concentrates.

BACKGROUND

Receptacle technology, and in particular capsule technology, continuesto be subject to development and improvements and so does themanufacture thereof, including processes and equipment. In its basicform, standard containers for pharmaceuticals or other powdered,granular or liquid substances (generally referred to as telescope-typeor two-piece capsules) include a tubular-shaped and/orcylindrically-shaped first part, namely a cap part, which is closed onone end and open on the other opposite end. A tightly fitting secondpart of similar shape, namely the body part, is of smaller diameter thanthe cap part and is typically telescopically engaged therein to form theoverall dosage form or two-piece capsule. Similar capsule technology maybe used to generate multi-compartment capsules.

Capsules generally comprise or are made of functional base shellmaterials (most commonly gelatin, but in more recent times alsoalternate polymers such as celluloses or pullulan) and other additivessuch as gelling agents, plasticizers and/or colorants.

In particular colorants have been typically employed specifically toprovide a vast sweet of color options for capsules and thus purely forproviding an aesthetic appearance sometimes linked to the branding ofthe ultimate dosage form. Such colorants are commonly syntheticallyderived colorants or selectively extracted pigments from natural sourcessince typically such materials tend to experience lesser fading withtime as well as particular resistance to thermal degradation.

Nevertheless, there is a desire for introduction of natural colorants inhard capsules, however this poses several challenges which have limitedtheir use in favor of synthetically derived or extracted colorants andpigments.

There is a desire to provide hard capsule compositions that containtruly natural colorants that provide for good physical and colorstability as well as added functionality and/or improved compatibilitywith aqueous based gelling systems used specifically in hard capsulemanufacture.

There is further a desire for colorants that allow their incorporationin capsule making compositions without further dispersion prior tomixing therewith.

SUMMARY

A first aspect of the present disclosure relates to an aqueouscomposition for making dip-molded comestible hard capsules comprising afilm forming capsule base material and one or more colorants whereineach said colorant consists of a hydrophilic coloring foodstuffconcentrate.

A further aspect of the present disclosure relates to a two-piece hardcapsule, the capsule comprising a film forming capsule base material andone or more colorants wherein each said colorant consists of ahydrophilic coloring foodstuff concentrate.

A further aspect of the present disclosure relates to a dip-moldingprocess for making two-piece hard capsules comprising the steps of:providing an aqueous composition comprising a film forming capsule basematerial; directly mixing one or more colorants each consisting ofhydrophilic coloring foodstuff concentrates with said aqueouscomposition to provide a dipping composition; dipping one or more moldpins in said dipping composition; extracting said one or more mold pinsfrom said dipping composition such that a film is formed over said pins;and drying said films to provide capsule shells.

A further aspect of the present disclosure relates to the use of one ormore colorants, each said colorant consisting of a hydrophilic coloringfoodstuff concentrate, in hard capsules, typically to provide a colorand a functional attribute to said capsule, said functional attributebeing selected from the group consisting of aromatic, sapid or nutritiveproperties

DETAILED DESCRIPTION

By the term “a” and/or “an” when describing a particular element, it isintended “at least one” of that particular element.

By the term “medicament”, it is intended a “drug” or the like comprisingone or more compounds providing one or more curative benefits to asubject, the terms “medicament” and “drug” may be used interchangeablyherein.

By the term “hard shell” or “hard capsule shell”, it is intended a shellthat is deformable, but which substantially returns to its un-deformedshape upon the removal of a deforming force. Typically such shellscomprise less than 25%, preferably less than 20%, more preferably from0% to 14%, even more preferably from greater than 0% to less than 14%,water by weight.

In the present disclosure, if not otherwise indicated, by “capsule” itis meant a hard capsule consisting of two co-axial,telescopically-joined parts, referred to as body and cap.

By the term “coloring foodstuff concentrate”, it is intended aconcentrate from a source material consisting of food or acharacteristic ingredient of food, and wherein the source material doesnot undergo selective physical and/or chemical extraction. Rather, thesource material is typically concentrated by traditionalgrinding/squeezing, dilution with non-organic solvent additives (such aswater, sugars such as inverted sugar (a non-crystalline version ofsucrose) or D-Trehalose, and citric acid (or derivatives thereof, liketrisodium citrate), followed by drying/evaporation (at temperatures notexceeding 240° C.). Typically such coloring foodstuff concentrate havingan enrichment factor Fe (also referred to as Fn) of less than 6.

By the term “directly mixing”, it is intended mixing directly in theelement referred to (e.g. a composition) without further dilution orsolubilization or other pre-mixing with further materials.

The term “relative humidity” is used herein to mean the ratio of theactual water vapor pressure at a given temperature to the vapor pressurethat would occur if the air were saturated at the same temperature.There are many technologies for humidity measurement instruments knownto the skilled person, all of which would give substantially the same RHmeasure.

By the term “hydrophilic”, it is intended that the material referred tohas strong affinity with water in that they form a solution when addedto water without phase splitting (or forming separate phases) generallydue to the material charge-polarized characteristics and capability ofhydrogen bonding.

By the term “carbohydrates”, it is intended mono- and oligo-saccharidesonly. Various embodiments will now be described to provide an overallunderstanding of the principles of the structure, function, manufacture,and use of dosage forms, uses, and methods disclosed herein. One or moreexamples of these embodiments are illustrated in the accompanyingfigures. Those of ordinary skill in the art will immediately understandthat features described or illustrated in connection with one exampleembodiment can be combined with the features of other exampleembodiments without generalization from the present disclosure.

The Composition

Compositions herein for making hard capsules comprise, preferablyconsist essentially of, a film forming capsule base material, one ormore colorants and water. Optionally, one or more further additives maybe comprised such as plasticizers, anti-bacterial-agents, andneutralizing agents (particularly alkaline materials). Such optionaladditives may be preferably comprised in the composition when the basematerial is selected from enteric cellulose materials such ashydroxypropyl methyl cellulose acetate succinate (HPMCAS) orhydroxypropyl methyl cellulose phthalate (HPMCP).

The film forming capsule base material may be selected from one or morecelluloses (like HPMC, HPMCP, HPMCAS, MC), gelatin, pullulan, andmixtures thereof. Most preferred are celluloses, and particularlyhydroxypropyl methylcellulose (HPMC).

The HPMC methoxy and hydroxypropoxy contents herein are expressedaccording to the USP30-NF25. The viscosity of the HPMC 2% weightsolution in water at 20° C. is measured according to the USP30-NF25method for cellulose derivatives.

Preferably the aqueous composition comprises 17-23% by weight, based onthe total weight of the aqueous composition, of the hydroxypropyl methylcellulose. Suitable hydroxypropyl methyl celluloses are commerciallyavailable. For example suitable types are all those fulfilling therequirements set forth in USP30-NF25 for HPMC type 2906.

Suitable aqueous compositions can be obtained by blending HPMCs of sametype but different viscosity grade.

In a preferred embodiment, the HPMC in the aqueous composition herein isa HPMC having a viscosity of 4.0 to 5.0 cPs as a 2% w/w solution inwater at 20° C.

Viscosity of the HPMC solution in water can be measured by conventionaltechniques, e.g. as disclosed in the USP by using a viscometer of theUbbelohde type.

In an embodiment, the aqueous compositions herein may contain between 0%and 5%, preferably between 0% and 2% by weight based on the total weightof the aqueous composition of additional non animal-derived film-formingpolymers typically used for the manufacture of hard capsules. In anembodiment, the HPMC aqueous compositions of the invention contain noother film-forming polymer beside the HPMC presently disclosed. Nonanimal-derived film-forming polymers are for example polyvinyl alcohol,plant-derived or bacterial-derived film-forming polymers. Typicalplant-derived film-forming polymers are starch, starch derivatives,cellulose, celluloses derivatives other than the HPMC as defined hereinand mixtures thereof. Typical bacterial-derived film-forming polymer areexo-polysaccharides. Typical exo-polysaccharides are xanthan, acetan,gellan, welan, rhamsan, furcelleran, succinoglycan, scleroglycan,schizophyllan, tamarind gum, curdlan, pullulan, dextran and mixturesthereof.

In a preferred embodiment, the HPMC aqueous compositions herein containbetween 0% and 1%, preferably 0% by weight based on the total weight ofthe aqueous composition of animal-derived materials conventionally usedfor the manufacture of hard capsules. A typical animal-derived materialis gelatin.

In a preferred embodiment, the aqueous compositions herein contain lessthan 0.2%, preferably less than 0.1%, preferably 0% (i.e. in mostpreferred embodiments the composition herein is free of gelling system)by weight based on the total weight of the aqueous composition of agelling system. By “gelling systems” it is meant one or more cationsand/or one or more gelling agents. Typical cations are K<+>, Na<+>,Li<+>, NH4<+>, Ca<++>, Mg<++> and mixtures thereof. Typical gellingagent(s) are hydrocolloids such as alginates, agar gum, guar gum, locustbean gum (carob), carrageenans, tara gum, gum arabic, ghatti gum, khayagrandifolia gum, tragacanth gum, karaya gum, pectin, arabian (araban),xanthan, gellan gum, konjac mannan, galactomannan, funoran, and mixturesthereof. As usually, gelling agents can optionally be used incombination with cations and other ingredients such as sequesteringagents.

As the HPMC aqueous compositions disclosed herein are suitable to givestrong and physically stable gels without gelling systems, thedissolution properties of the HPMC capsules of the invention are notaffected by the drawbacks typically associated with gelling systems,notably cations.

At the natural state—i.e. without the addition of colorants or similaringredients in the composition—the HPMC hard capsules obtainable fromthe aqueous compositions herein show good clarity and transparency. Thetransmittance measured by UV at 650 nm on the capsule body (through itsdouble shell layers) is around 80%, identical to gelatine hard capsules.

Colorants for use in compositions describered herein are naturalcolorants or coloring foodstuff concentrates. Such colorants areselected such to consist of ones being hydrophilic, since such have beenfound to be particularly useful in mixing in aqueous hard capsulecompositions leading to improved stability of the resulting capsules. Anadvantage is to additionally not require addition of further materialssuch as anti-oxidants, preservatives, vitamins and the like for addedfunctionality, and further enables the incorporation of such colorantsdirectly into the aqueous film forming composition without furtherdilution/dispersion into other media that typicaly would includesurfactants, dispersants and solvents (e.g. organic solvents).

The colorants may be liquid in form or in powder form the lattertypically by atomization process or preferably freeze-dried. If inpowder there are preferably in freeze-dried powder form, since it hasbeen advantageously found that their dispersion capabilities in aqueouscompositions for dip-molded capsules is well retained. Most preferredcolorants are however in liquid form.

Generally, 0.01 to 10.0%, preferably 0.1 to 8%, more preferably 1% to7%, even more preferably 2% to 6%, even more preferably from 3.5% to5.5%, by weight of colorant can be included in the aqueous composition.The weight is expressed over the total weight of the composition.Optionally, an appropriate plasticizer such as glycerine or propyleneglycol can be included in the aqueous solutions. To avoid an excessivesoftness, the plasticizer content has to be low, such as between 0% and2%, more preferably between 0% and 1% by weight over the total weight ofthe composition.

The coloring foodstuff concentrates typically have an enrichment factor(Fe) of less than 6, preferably less than 5.5, more preferably less than5, even more preferably less than 4.5, most preferably from 1 to 4.4, asmeasured according to the method described herein. An advantage of thisembodiment is to provide a natural colorant that may provide additionalfunctional (in particular aromatic, sapid or nutritive) attributes tothe resulting capsule. A further advantage is the addition of such addedfunctionality to the resulting hard capsule shells without adding anyfurther materials during the preparation of the aqueous compositionwhich may negatively alter the resulting stability thereof.

In a preferred embodiment, the composition is free of organic solvents,and is particularly free of at least ethanol or acetone, preferably freeof solvents selected from the group consisting of ethanol, acetone,ethyl acetate, butyl acetate, and mixtures thereof.

The source material of the coloring foodstuff concentrates is typicallyselected from the group consisting of vegetables, preferably selectedfrom purple carrot, pumpkin, yam, radish, sweet potato, beetroot, andmixtures thereof; fruits, preferably selected from elderberry,blackcurrant, grape, apple, huito, and mixtures thereof; comestibleplants; algae; fungi preferably selected from safflower, carthamus,hibiscus, tropaeolum, spirulina, chlorella, and mixtures thereof; andmixture thereof. It has been found that such materials result inacceptable physically and light stable colored capsules.

Most preferred source materials are selected from the group consistingof purple carrot, sweet potato, safflower, spirulina, and mixturesthereof. Such provide satisfactory physical and light stability and arefound to be very well suited for mixtures for providing different colorshades.

Source materials that are less preferred typically include orange,curcuma, tomato and carrot (or other carotene dispersions). Suchtypically have been found to have innate characteristics of the foodproduct which make them less suitable for the particular use in hardcapsule manufacture, particularly due to pH sensitivity as well as poorlight stability over time.

Colorants not suitable, and thus presently generally excluded by thedisclosure, include the following non-limiting list of materials: R3(erythrosine B), R3 opaque (erythrosine B), Y6 (sunset yellow), Y6opaque (sunset yellow), B2 (indigotine), B2 opaque (indigotine), Y5(tartrazine), Y5 opaque (tartrazine), R40 (allura red), R40 opaque(allura red), Y10 (quinolein), Y10 opaque (quinolein), synthetic tarpigment, iron oxide, titanium dioxide or carbon black, carotenoid-basedpigments, annatto dye (for example, bixin, norbixin), gardenia yellowpigment (for example crocin), extracted carrot pigment (for exampleβ-carotene), extracted orange pigment (for example β-apo-β-carotenal),extracted paprika pigment (For example capsanthin), extracted mushroompigment (eg canthaxanthin), extracted tomato pigment (for example,lycopene), and the like, extracted purple sweet potato pigmentanthocyanin systems, extracted grape skin pigment (for exampleEnoshianin), extracted perilla pigment (for example shisonin), extractedred cabbage pigment (for example Le Bro brush true), extracted chalconeof the safflower yellow pigment, extracted buckwheat pigment (forexample rutin), extracted black oak skin pigment (eg quercetin),extracted sorghum pigment (for example apigenin), extracted cacaopigment, laccaic acid, carmine acid, alizarin, and the like,powdered/extracted catechutannic acid, extracted turmeric,methylrosanilinium chloride, yellow iron oxide, yellow iron sesquioxide,orange essence, brown iron oxide, carbon black, carmine, caroteneliquid, β-carotene, light sensitive element No. 201, gold leaf, sasaalbomarginata extract, black iron oxide, light anhydrous silicic acid,zinc oxide, titanium oxide, iron sesquioxide, disazo yellow, food blueNo. 1 and its aluminum lake, food blue No. 2 and its aluminum lake, foodYellow No. 4 and its aluminum lake, food Yellow No. 5 and its aluminumlake, food Green No. 3 and its aluminum lake, food red No. 2 and thealuminum lake, food red No. 3, food red No. 102 and its aluminum lake,food red No. 104 and its aluminum lake, food red No. 105 and itsaluminum lake, food Red No 106 and its aluminum lake, sodium hydroxide,talc, copper chlorophyll sodium, copper chlorophyll, rye green leafextract, phenol red, sodium fluorescein, d-borneol, malachite green,octyl dodecyl myristate, methylene blue, medicinal carbon, riboflavinbutyrate, riboflavin, manganese ammonium phosphate, riboflavin sodiumphosphate, rose oil, turmeric color, chlorophyll, carminic acid color,food red No. 40 and its aluminum lake, sodium iron-chlorophyllin,dunaliella carotene, paprika colour, ginseng carotene, potassiumnorbixin, sodium norbixin, palm oil carotene, extracted beet red,extracted grape pericarp color, extracted black currant color, extractedmonascus color, extracted safflower red color, extracted marigold color,sodium riboflavine phosphate, madder color, alkanet color, aluminum,potato carotene, extracted shrimp color, extracted krill color,extracted orange color, extracted cacao color, extracted cacaocarbon-dust color, extracted oyster color, extracted crab color,extracted carob color, extracted fish scale foil, silver, extractedkusagi color, extracted gardenia blue color, extracted gardenia redcolor, extracted gardenia yellow color and kooroo color, chlorophine,extracted kaoliang color, extracted bone char color, extracted bamboograss color, extracted shea nut color, extracted lithosperm root color,extracted redsanders color, vegetable carbon black, extracted sappancolor, extracted onion color, extracted tamarind color, extracted corncolor, extracted tomato color, extracted peanut color, extracted phaffiacolor, pecan nut color, extracted monascus yellow, extractedhematococcus algae color, extracted purple sweet potato pigment,extracted purple corn color, extracted purple yam color, vegetable oilsoot color, lac color, rutin, enju extract, backwheat extract, logwoodcolor, extracted red cabbage color, extracted red rice color, extractedazuki color, extracted hydrangeae leaves extract, uguisukagura color,extracted elderberry color, extracted olive tea color, extractedcowberry color, extracted gooseberry color, extracted cranberry color,extracted salmon berry color, extracted strawberry color, extracted darksweet cherry color, extracted cherry color, extracted thimbleberrycolor, extracted deberry color, extracted pineapple color, extractedhuckleberry color, extracted grape juice color, extracted black currantcolor, extracted blackberry color, extracted plum color, extractedblueberry color, extracted berry color, extracted boysenberry color,extracted whortleberry color, extracted mulberry color, extractedmorello cherry color, extracted raspberry color, extracted red currantcolor, extracted lemon juice color, extracted loganberry color,extracted cocoa color, extracted saffron color, extracted beefsteakplant color, extracted chicory color, extracted layer color, extractedhibiscus color, malt extract, extracted powdered paprika, extracted beetred color, extracted ginseng color, and the like.

Colorants that are generally particularly excluded by the disclosureinclude lipophilic beta-carotene pigments, hydrophilic flavonoids,chlorophyll and/or phycocyanin pigments. Indeed such are examples ofextracted pigments. Moreover, carotenoids are generally lipophilic,requiring thus additional species such as dispersing gents orsurfactants, to be able to incorporate them into water-basedcompositions.

The compositions described herein may further comprise opacifiers (liketitanium oxide), however, if present, such are in amounts of less than1.5%, preferably less than 0.5%, more preferably less than 0.2%, evenmore preferably less than 0.1%, and more preferably 0% (i.e. free ofopacifiers), by weight of the composition.

It has been noted that the aqueous compositions herein allow themanufacture of good, particularly HPMC, hard capsules showing optimaldissolution properties. Dissolution profile is a key point in therapy toobtain a complete and reproducible release of the substance contained inthe capsule.

Additionally, it has been noted that the aqueous compositions hereinallow the manufacture of good hard capsules whose bodies and caps, oncetelescopically joined, can suitably be sealed. This makes the presentlydisclosed new hard capsules a particularly good and cost-effectivesolution for the manufacture of liquid-filled oral dosage forms as wellas powder-filled dosage forms for inhalation or the manufacture oftamper-proof pharmaceutical forms to be used in the context ofdouble-blind trials.

The Dosage Form Article

Dosage form articles herein are in the form of hard capsules thatprovide at least one compartment for filling a medicament therein. Suchhard capsules comprise at least two shells (forming a two-piece hardcapsule) typically comprising a body part and a cap part telescopicallyfitted therover.

In a preferred embodiment, the capsule shells are obtainable by theaqueous composition and/or process disclosed herein.

The hard capsules herein comprise a film forming capsule base materialand one or more colorants each colorant consisting of a hydrophiliccoloring foodstuff concentrate described herein above.

In a preferred embodiment, the capsule has a color stability, ΔE₂₀₀₀,after 5 weeks under constant illumination (as described in the testmethod herein) storage at room temperature, of less than 16, preferablyless than 15, more preferably less than 12, even more preferably from 1to 11, most preferably from 2 to 10. Advantageously, it has been foundthat capsules meeting such parameter show good light stability andminimal fading with time under in use production, storage and ultimateuse conditions.

In a preferred embodiment, the capsule shell contains HPMC in an amountbetween 70 and 99%, preferably between 80 and 99% by weight based on theshell weight. If no other film-forming polymers are present, the HPMC ispreferably between 92% and 99%, more preferably between 93 and 98%, evenmore preferably between 94% and 97% by weight based on the shell weight.In a preferred embodiment, the capsule shell contains between 0% and25%, preferably between 0% and 10% by weight based on the shell weightof additional non animal-derived film-forming polymers as defined above.

In a preferred embodiment, the capsule shell contains water between 1 to8%, preferably between 2 and 7%, more preferably between 3 and 6% byweight based on the empty shell weight (measured at room temperature andpressure and relative humidity RH of about 50%).

In a preferred embodiment, the colorants discussed above are comprisedin the capsule in a total amount of, between 0 and 10%, preferablybetween 0.001 and 5%, more preferably between 0.01 and 3%, by weightbased on the empty shell weight.

In an embodiment, the capsule shell contains one or more plasticizers ina total amount of, between 0 and 10%, preferably between 0.001 and 5%,more preferably between 0.01 and 3%, by weight based on the empty shellweight.

In an embodiment, the capsule shell contains one or more antibacterialagents between 0 and 2%, preferably between 0.001 and 1%, morepreferably between 0.01 and 0.5%, by weight based on the shell weight.

In an embodiment, the capsule shell contains one or more flavouringsagents between 0 and 2%, preferably between 0.001 and 1%, morepreferably between 0.01 and 0.5%, by weight based on the shell weight.

In a preferred embodiment, the hard capsule shell presently disclosedcan be used for the manufacture of tamper-proof pharmaceutical dosageforms. To this end, it is particularly advantageous if the capsule shellis as disclosed in EP 110500 B1. In this preferred embodiment, the,preferably HPMC, hard capsule shell comprises coaxial cap and body eachof the cap and body having a generally cylindrical side wall, an openend and a closed end region, the side wall of each of said parts issubstantially greater than the capsule shell diameter, the cap and bodybeing adapted to be joined in telescopic relationship wherein, when thecap and body are fully joined in telescopic relationship, the onlyportion of the body which is exposed is the closed end region, andwherein the closed end region has an outer surface which is of such aconfiguration as to resist being gripped, whereby separation of the capand body is impeded, and wherein when the cap and body are fully joinedin telescopic relationship, the inner side wall of the cap issubstantially totally overlapped by the outer side wall of the body. Inother words, when the cap and body are fully joined in telescopicrelationship, the side wall of the cap encases the entire side wall ofthe body. Thus, in use, only the body closed end is exposed and presentsa minimal surface for gripping and withdrawal of the body from withinthe cap, thereby impeding separation of the capsule shell.

The closed end region of either the body and the cap may, for example,have a configuration which is generally hemispheroidal, pyramidal,conical or flat.

For additional security, it is preferred that the body and the capfurther include mutual locking means comprising one or morecircumferentially extending ridges and/or grooves. Thus, the capsuleshell may be such that the side wall of one of the cap and body has alocking means comprising one or more circumferentially extending ridgeextending either (i) radially inwardly from an inner surface of the sidewall of the cap or (ii) radially outwardly from an outer surface of theside wall of the body, as the case may be.

Alternatively, or in addition, the side wall of the other of the cap andbody has one or more circumferentially extending groove extending either(i) radially inwardly from the outer surface of the body or (ii)radially outwardly from the inner surface of the cap, as the case maybe, and engaging a respective ridge.

It is preferred that the capsule shell further includes venting means topermit air to escape from within the capsule when joined, wherein the oreach circumferentially extending ridge comprises two or more segments sothat spaces between the segments act as vents to permit air to escapefrom within the capsule when the cap and body are being joined.

It is preferred that the side wall of one of the cap and body has a pairof diametrically opposed integral indents extending either (i) radiallyinwardly from the inner surface of the side wall of the cap or (ii)radially outwardly from the outer surface of the side wall of the body,as the case may be; and the diametric spacing of the indents is, in thecase (i), less than the outside diameter of the open end of the body or,in the case (ii), greater than the inside diameter of the open end ofthe cap, such that the body can enter the cap and permit air to escapefrom within the capsule when the cap and body are being joined.

For storage and/or transportation purposes, it is preferred that thecapsule shell may also include means for pre-locking the partiallyjoined caps and bodies in a constant predetermined relative positionprior to filling and final joining.

Preferably, bodies have a reduced diameter in the area of their open endin order to avoid abutment when they are telescopically housed withincaps.

Alternatively, or in addition, caps have a reduced diameter in the areaof their open end, thereby resulting in improved engagement between themand the region of the side wall of the bodies adjacent the closed endregion of the bodies, as further resistance to tampering.

In an aspect, the present disclosure relates to a hard capsule definedabove comprising a capsule shell as defined above and one or moremedicaments filled therein.

When used as dosage form for drugs, capsules of the invention typicallycomprise for example from 0.001 g to 2.0 g of active ingredient,optionally mixed with one or more pharmaceutically acceptableexcipients.

In one embodiment, the, preferably HPMC, hard capsule presentlydisclosed, optionally sealed, can be used in the context of dry powderinhalers (also commonly know by the acronym DPIs).

Medicament

Drugs (i.e. medicaments) suitable for use in the dosage form articlesdescribed herein may take any form and be for any treatment of a humanor animal subject. This includes not only pharmaceutical compounds butalso dietary supplements such as vitamins, minerals and the like.

The drug may be in a state selected from solid or liquid, preferablysolid, at room temperature and atmospheric pressure, and comprises oneor more active compounds.

Suitable compounds (and generally encompassed by the term “medicament”as used herein) for delivery according to the disclosure include, butare not limited to, particulate, powder, waxy, liquid, and/or pelletforms of the following:

-   -   a) pharmaceuticals (also called pharmaceutical actives) such as        betamethasone, thioctic acid, sotalol, salbutamol, norfenefrine,        silymahn, dihydroergotamine, buflomedil, etofibrate,        indomethacin, oxazepam, acetyldigitoxins, piroxicam, halopehdol,        isosorbide mononitrate, amithptyline, diclofenac, nifedipine,        verapamil, pyritinol, nitrendipine, doxy-cycline, bromhexine,        methylprednisolone, clonidine, fenofibrate, allopurinol,        pirenzepine, levothyroxine, tamoxifen, metildigoxin,        o-(B-hydroxyethyl)-rutoside, propicillin, aciclovir-mononitrate,        paracetamolol, naftidrofuryl, pentoxifylline, propafenone,        acebutolol, 1-thyroxin, tramadol, bromocriptine, loperamide,        ketofinen, fenoterol, ca-dobesilate, propranolol, minocycline,        nicergoline, ambroxol, metoprolol, B-sitosterin,        enalaprilhydro-genmaleate, bezafibrate, isosorbide dinitrate,        gallopamil, xantinolnicotinate, digitoxin, flunitrazepam,        bencyclane, depanthenol, pindolol, lorazepam, diltiazem,        piracetam, phenoxymethylpenicillin, furosemide, bromazepam,        flunarizine, erythromycin, metoclopramide, acemetacin,        ranitidine, biperiden, metamizol, doxepin,        dipotassiumchloraze-pat, tetrazepam, estramustinephosphate,        terbutaline, captopril, maprotiline, prazosin, atenolol,        glibenclamid, cefaclor, etilefrin, cimetidine, theophylline,        hydromorphone, ibu-profen, primidone, clobazam, oxaceprol,        medroxyprogesterone, flecainide,        Mg-pyhdoxal-5-phosphateglutaminate, hymechromone,        etofyllineclofibrate, vincamine, cin-narizine, diazepam,        ketoprofen, flupentixol, molsidomine, glibornuhde, dimethindene,        melperone, soquinolol, dihydrocodeine, clomethiazole,        clemastine, glisoxepid, kallidino-genase, oxyfedhne, baclofen,        carboxymethylcystsin, thioredoxin, betahistine, 1-tryptophan,        myrtol, bromelain, prenylamine, salazosulfapyridine, astemizole,        sulpiride, benzerazid, dibenzepin, acetylsalicylic acid,        miconazole, nystatin, ketoconazole, sodium picosulfate,        colestyramate, gemfibrozil, rifampin, fluocortolone, mexiletine,        amoxicillin, terfenadine, mucopolysaccharidpolysulfuric acid,        triazolam, mianserin, tiaprofensaure, ameziniummethylsulfate,        mefloquine, probucol, quinidine, carbamazepine, Mg-1-aspartate,        penbutolol, piretanide, amitriptyline, caproteron, sodium        valproinate, me-beverine, bisacodyl, 5-amino-salicyclic acid,        dihydralazine, magaldrate, phenprocou-mon, amantadine, naproxen,        carteolol, famotidine, methyldopa, auranofine, estriol, nadolol,        levomepromazine, doxorubicin, medofenoxat, azathioprine,        flutamide, norfloxacin, fendiline, prajmaliumbitartrate, aescin        acromycin, anipamil, benzocaine, [beta]-carotene,        cloramphenicol, chlorodiazepoxid, chlormadinoneacetate,        chlorothiazide, cin-narizine, clonazepam, codeine,        dexamethasone, dicumarol, digoxin, drotaverine, grami-cidine,        griseofulvin, hexobarbital hydrochlorothiazide, hydrocortisone,        hydroflumethiazide, ketoprofen, lonetil, medazepam, mefruside,        methandrostenolone, sulfaperine, nalidixic acid, nitrazepam,        nitrofurantoin, estradiol, papaverine, phenacetin,        phenobarbi-tal, phenylbutazone, phenytoin, prednisone,        reserpine, spironolactine, streptomycin, sul-famethizole,        sulfamethazine, sulfamethoxoazole, sulfamethoxydiazinon,        sulfathiazole, sulfisoxazole, testosterone, tolazamide,        tolbutamide, trimethoprim, tyrothricin, antacids, reflux        suppressants, antiflatulents, antidopaminergics, proton pump        inhibitors, H2-receptor antagonists, cytoprotectants,        prostaglandin analogues, laxatives, antispasmodics,        antidiarrhoeals, bile acid sequestrants, opioids, beta-receptor        blockers, calcium channel blockers, diuretics, cardiac        glycosides, antiarrhythmics, nitrates, antianginals,        vasoconstrictors, vasodilators, ACE inhibitors, angiotensin        receptor blockers, alpha blockers, anticoagulants, heparin,        antiplatelet drugs, fibrinolytic, anti-hemophilic factor,        haemostatic drugs, hypolipidaemic agents, statins, hypnotics,        anaesthetics, antipsychotics, antidepressants (including        tricyclic antidepressants, monoamine oxidase inhibitors, lithium        salts, selective serotonin reuptake inhibitors), anti-emetics,        anticonvulsants, an-tiepileptics, anxiolytics, barbiturates,        movement disorder drugs, stimulants (including amphetamines),        benzodiazepine, cyclopyrrolone, dopamine antagonists,        antihistamines, cholinergics, anticholinergics, emetics,        cannabinoids, 5-HT antagonists, analgesics, muscle relaxants,        antibiotics, sulfa drugs, aminoglycosides, fluoroquinolones,        bronchodilators, NSAIDs, anti-allergy drugs, antitussives,        mucolytics, decongestants, corticosteroids, beta-receptor        antagonists, anticholinergics, steroids, androgens,        antian-drogens, gonadotropin, corticosteroids, growth hormones,        insulin, antidiabetic drugs (including sulfonylurea,        biguanide/metformin, and thiazolidinedione), thyroid hormones,        antithyroid drugs, calcitonin, diphosponate, vasopressin        analogs, contraceptives, follicle stimulating hormone,        luteinising hormone, gonadotropin release inhibitor,        progestogen, dopamine agonists, oestrogen, prostaglandin,        gonadorelin, clomiphene, tamoxifen, di-ethylsti I bestrol,        antimalarials, anthelmintics, amoebicides, antivirals,        antiprotozoals, vaccines, immunoglobulin, immunosuppressants,        interferon, monoclonal antibodies, and mixtures thereof;

b) vitamins, e.g., fat-soluble vitamins such as vitamins A, D, E, and K,and water soluble vitamins such as vitamin C, biotin, folate, niacin,pantothenic acid, riboflavin, thiamin, vitamin B6, vitamin B12, andmixtures thereof;

c) minerals, such as calcium, chromium, copper, fluoride, iodine, iron,magnesium, manganese, molybdenum, phosphorus, potassium, selenium,sodium (including sodium chloride), zinc, and mixtures thereof;

d) dietary supplements such as herbs or other botanicals, amino acids,and substances such as enzymes, organ tissues, glandulars, andmetabolites, as well as concentrates, metabolites, constituents,extracts of dietary ingredients, oils such as krill oil and mixturesthereof;

e) homoeopathic ingredients such as those listed in the HomeopathicPharmacopoeia of the United States Revision Service (HPRS), and mixturesthereof. It must be recognized, of course, that the HPRS is periodicallyupdated and that the present invention includes homeopathic ingredientsthat may be added to the HPRS;

f) probiotics and yeast, such as bacteria selected from the groupconsisting of Lactobacillus (Döderlein's bacilli) such as Lactobacilluscrispatus, Lactobacillus jensinii, Lactobacillus johnsonii,Lactobacillus gasseri, Enterococcus faecium, or fungi selected from thegroup of Saccharomycetales such as Saccharomyces boulardii.

g) hormones, such as estrogen (i.e. a natural estrogen or a syntheticcompound that mimics the physiological effect of natural estrogens)including, without limitation, estradiol (17-estradiol), estridiolacetate, estradiol benzoate, estridiol cypionate, estridiol decanoate,estradiol diacetate, estradiol heptanoate, estradiol valerate,17a-estradiol, estriol, estriol succinate, estrone, estrone acetate,estrone sulfate, estropipate (piperazine estrone sulfate),ethynylestradiol (17a-ethynylestradiol, ethinylestradiol, ethinylestradiol, ethynyl estradiol), ethynylestradiol 3-acetate,ethynylestradiol 3-benzoate, mestranol, quinestrol, nitrated estrogenderivatives or combinations thereof; or progestin (i.e. natural orsynthetic compounds that possesses progestational activity including,without limitation, nortestosterone, ethynyltestosterone,deacetylnorgestimate, hydroxyprogesterone, 19-norprogesterone,3P-hydroxydesogestrel, 3-ketodesogestrel (etonogestrel),acetoxypregnenolone, algestone acetophenide, allylestrenol, amgestone,anagestone acetate, chlormadinone, chlormadinone acetate, cyproterone,cyproterone acetate, demegestone, desogestrel, dienogest,dihydrogesterone, dimethisterone, drospirenone, dydrogesterone,ethisterone (pregneninolone, 17a-ethynyltestosterone), ethynodioldiacetate, fluorogestone acetate, gastrinone, gestadene, gestodene,gestonorone, gestrinone, hydroxymethylprogesterone,hydroxymethylprogesterone acetate, hydroxyprogesterone,hydroxyprogesterone acetate, hydroxyprogesterone caproate,levonorgestrel (1-norgestrol), lynestrenol (lynoestrenol),mecirogestone, medrogestone, medroxyprogesterone, medroxyprogesteroneacetate, megestrol, megestrol acetate, melengestrol, melengestrolacetate, nestorone, nomegestrol, norelgestromin, norethindrone(norethisterone) (19-nor-17a-ethynyltestosterone), norethindrone acetate(norethisterone acetate), norethynodrel, norgestimate, norgestrel(d-norgestrel and dl-norgestrel), norgestrienone, normethisterone,progesterone, promegestone, quingestanol, tanaproget, tibolone,trimegestone, or combinations thereof. And mixtures in any combinationof the foregoing.

The Processes and Uses

The aqueous compositions described herein are typically used as dippingcompositions in dip-molding processes for the manufacture of hardcapsules.

Dip-molding processes for making two-piece hard capsules herein comprisethe steps of: providing an aqueous composition comprising a film formingcapsule base material;

directly mixing one or more colorants each consisting of hydrophiliccoloring foodstuff concentrates with said aqueous composition to providea dipping composition;

dipping one or more mold pins in said dipping composition;

extracting said one or more mold pins from said dipping composition suchthat a film is formed over said pins; and

drying said films to provide capsule shells.

The most preferred film forming capsule base material comprises,preferably consists of, one or more celluloses such as hydroxypropylmethylcellulose (HPMC). Such has the advantage of enabling a lowercomposition temperature during the dipping thermogelation process (coldgelation process) which limits the color degradation and/or instabilityof the selected coloring foodstuff concentrates. Thus the “coldgelation” (thermogelation) process with HPMC, where the dip compositionis kept at a temperature below gelation and rather the mold pins areheated at temperatures above gelation prior immersion therein, isparticularly preferred and selected for generating physically stablehard capsules comprising natural colorants (or hydrophilic coloringfoodstuff concentrate) described herein. Such has the further advantageof resulting in fully vegetarian dosage forms with better patienceacceptance by some particular groups of subjects (e.g. having dietary orreligious requirements) whilst for example allowing higher levels ofsuch colorants to be incorporated for effectively providing furtherfunctional attributes to the capsules as described herein.

In a preferred embodiment, the aqueous composition is kept at atemperature of from 25° C. to 45° C., preferably from 30° C. to 40° C.Typically, in such embodiments film forming is achieved by cold gelationand the pins are as such pre-heated to a temperature that is greaterthan the gelation temperature of the composition prior to the dippingstep.

In a preferred embodiment, the aqueous composition and the dippingcomposition have a pH of less than 6, preferably less than 5, morepreferably from 3 to 4.9, even more preferably from 3.5 to 4.8, mostpreferably from 4.0 to 4.7. Such pH range has been found particularlybeneficial to avoid degradation of the particular natural colorantsdescribed above and as such improve stability of the composition andresulting capsules.

The drying step is preferably carried out at a temperature of less than65° C., preferably less than 60° C., even more preferably from 40° C. to55° C. Advantageously such temperatures still enable effective drying ofthe hard capsules without degradation of the natural colorants.

In an embodiment, the aqueous compositions herein can be prepared bydispersing the capsule base film forming material (e.g. HPMC) and theother optional ingredients in water. The aqueous solvent can be at atemperature above room temperature, preferably below 60° C., morepreferably below 50° C. In a preferred embodiment after de-bubbling, thedispersion is cooled down below room temperature, preferably below 15°C., to achieve the solubilisation of the cellulose (e.g HPMC).

The gelling temperature of the aqueous compositions may be determined bya measurement of the viscosity by progressively heating the composition.The temperature at which the viscosity starts to sharply increase isconsidered as the gelling temperature. As an example, for aconcentration of about 19% w/w in water, any HPMC of the inventionfulfilling the USP definition of HPMC type 2906 has a gellingtemperature of about between 30 and 40° C. As an additional example, forconcentrations between 15 and 25% w/w in water, an HPMC of the inventionfulfilling the USP definition of HPMC with a hydroxypropoxy content ofabout 6%, has a gelling temperature between about 30 and 40° C.

In an aspect, the present disclosure relates to a process for themanufacture of hydroxypropyl methyl cellulose hard capsules according toa dip coating process, characterized in that it comprises the steps of:(a) providing an aqueous composition of a hydroxypropyl methyl cellulosehaving a methoxy content of 27.0-30.0% (w/w), a hydroxypropoxy contentof 4.0-7.5% (w/w) and a viscosity of 3.5-6.0 cPs as a 2% weight solutionin water at 20° C., wherein the concentration of the hydroxypropylmethyl cellulose in the aqueous composition is chosen to obtain aviscosity of the aqueous composition of 1000 to 3000 cPs, preferably1200 to 2500 cPs, more preferably 1600 to 2000 cPs, measured at atemperature of 10° C. to 1.0<0>C below the aqueous composition gellingtemperature; (b) mixing the aqueous composition with one or morecolorants each consisting of hydrophilic coloring foodstuffconcentrates; (c) pre-heating dipping pins so that they are at 55-95° C.when dipped into the aqueous composition; (d) dipping the pre-heateddipping pins into the aqueous composition maintained at a temperature of1° C. to 10° C. below its gelling temperature; (e) withdrawing thedipping pins from the aqueous composition obtaining a film on thedipping pins and (f) drying the film on the dipping pins at atemperature above the gelling temperature of the aqueous composition soas to obtain molded capsule shells on the pins. Steps teps (a) and (b)and (d) to (f) are typically to be performed in the order they arepresented.

In step (a) the aqueous compositions of the invention can be used. Anoptional adjustment of the HPMC concentration can be performed to meetthe viscosity ranges indicated above.

In step (c), the temperature range of pre-heated pins is 55-95° C.meaning that this is the pin temperature when pins are dipped.Preferably the temperature is 60-90° C., more preferably 60-85° C., morepreferably 65-85° C., even more preferably 70-80° C. It is preferredthat such temperature be chosen according to the desired capsule size.By “according to the capsule size” it is meant that the smaller the pindimension, the higher the temperature. For example, for an HPMC type2906 (USP classification) and within the HPMC weight ranges definedabove for the aqueous composition, for a capsule size 00 (conventionallyconsidered a large capsule size), the pin temperature is preferablybetween 70 and 80, for a capsule size 1 (conventionally considered amedium capsule size), the pin temperature is preferably between 80 and90, and for a capsule size 4 (conventionally considered a small capsulesize), the pin temperature is preferably between 85 and 95.

In step (d), the dipping composition is maintained at a temperature of10° C. to 1.0° C., preferably 6° C. to 2.0° C., below its gellingtemperature. For example, if a dipping composition has a gellingtemperature of about 36.0° C., it can be maintained at a temperature offor example about 34.0° C.

After being withdrawn from the dipping composition, the pins can beturned from a “top-down” dipping position to a “top-up” drying positionaccording to conventional capsule molding processes. In this step thepins are rotated about a horizontal axis of about 180° with respect tothe dipping position of step (d).

By drying in step (f) the object is to reduce the water content in thecapsule shells on the pins. Generally, the water content in the moldedcapsule shells is reduced from around 80% to around 7% by weight, basedon the total weight of the molded capsule shells. Step (f) is typicallycarried out for a period of time of from 30 to 60 minutes, preferablynot exceeding the above identified temperatures.

Normally, caps and bodies have a side wall, an open end and a closedend. The length of the side wall of each of said parts is generallygreater than the capsule diameter. Thus, the hard capsules of thepresent disclosure do not structurally depart from the conventionaldefinition of hard capsules. “Capsule” refers to both empty and filledcapsules.

The molded capsule shells mentioned to above, generally refer to bothbodies and caps, depending on the shape of the mold pin. Thus, afterstep (e) the dried capsule shells on the dipping pins can be processedaccording to conventional steps. This means that in general after step(e), the capsule shells (bodies and caps) are stripped from the pins.This step can be followed by cutting the stripped shells to a desiredlength.

Typically, hard capsule dip-molding manufacturing processes encompass anadditional step of lubricating the pins so as to make it easier to stripthe capsule shells from the pins. Lubrication is normally achieved viathe application of a demolding agent to the pins surface.

Once filled, the capsules can be made tamper-proof by using any solutionconventionally used in the field of hard capsules to make the jointpermanent. Banding or sealing are suitable techniques. Sealing is atechnique well known in the field of hard shell capsules. Variousalternative techniques are currently used for this purpose. A suitableprocedure is disclosed for example in U.S. Pat. Nos. 4,539,060 and4,656,066. Many improvements of sealing procedure are currentlyavailable.

According to a know sealing process, the capsule is (i) contacted with asealing fluid, (ii) excess sealing fluid is removed from the surface and(iii) the capsule is dried so as to induce curing and make the sealpermanent.

For example alcohol/water mixtures can be used as sealing fluids, suchas ethanol/water mixtures. The good sealing quality obtained makes thesealed capsule of the disclosure particularly suitable for themanufacture of leakage-free dosage forms particularly for use in theadministration of substances in liquid form. By “sealing quality” it ismeant either the visual quality and/or the adhesion strength of thesealing.

The above aqueous compositions and process are particularly suitable formanufacturing HPMC hard capsules that dissolve at a rate comparable toconventional gelatine capsules. Such capsules can be manufactured at anindustrial scale with process speeds comparable to gelatine capsules.Their mechanical properties are better than those of conventionalgelatine capsules since they are less brittle, particularly underextremely dry atmosphere. Their visual appearance is similar to that ofgelatine capsules.

A preferred aspect of the disclosure consists of the use of one or morecolorants, each said colorant consisting of a hydrophilic coloringfoodstuff concentrate (generally as described above), in hard capsules,typically to provide a color and a functional attribute to said capsule,said functional attribute being selected from the group consisting ofaromatic, sapid or nutritive properties. Such hydrophilic coloringfoodstuff concentrate preferably selected from concentrates of carrot,purple carrot, pumpkin, yam, radish, sweet potato, beetroot, elderberry,blackcurrant, grape, apple, huito, safflower, carthamus, hibiscus,tropaeolum, spirulina, chlorella, and mixtures thereof, preferablypurple carrot, sweet potato, safflower, spirulina, and mixtures thereof.

The scope of the invention can be understood better by referring to theexamples given below, the aim of which is to explain the advantages ofthe invention. Unless otherwise specified, all parts and percentages areby weight. Composition viscosities were determined by Brookfieldviscometer.

Test Methods Color Stability

Color stability is carried out in an accelerated constraining testcondition via a light-climate test cabinet with temperature regulationand 2 light sources comprising a cool white fluorescent lamp and a nearUV fluorescent lamp and following the procedure outlined in: ICHharmonised tripartite guideline, stability testing: photostabilitytesting of new drug substances and products Q1B, 6 November 1996 (thewhole contents of which is herein included by reference). The test isset to reach 1.2 Mio Lux⋅hours threshold (e.g. after a 5 weekintense/accelerated exposure/storage with an Incubator BCR 240 fromFirlabo).

A. Light Source

The light sources described below is used for photostability testing.The temperature is controlled to minimize the effect of localizedtemperature changes and a dark control is included in the sameenvironment.

The same sample is exposed to both the cool white fluorescent and nearultraviolet lamp. 1. A cool white fluorescent lamp designed to producean output similar to that specified in ISO 10977(1993); and 2. A near UVfluorescent lamp having a spectral distribution from 320 nm to 400 nmwith a maximum energy emission between 350 nm and 370 nm; a significantproportion of UV should be in both bands of 320 to 360 nm and 360 to 400nm.

B. Procedure

Samples are exposed to light providing an overall illumination of about1.2 million lux hours and an integrated near ultraviolet energy of about200 watt hours/square meter.

Samples are exposed side-by-side with a validated chemical actinometricsystem to ensure the specified light exposure is obtained, or for theappropriate duration of time when conditions have been monitored usingcalibrated radiometers/lux meters.

For the dark control, samples are wrapped in aluminum foil and placedalongside the rest of the samples.

HPMC capsules are made according to the dip-molding process hereindescribed comprising a number of different coloring agents to generatesamples for the color stability test. The formulation of Example 1 isrepeated for the different coloring materials to generate samples ofeach capsule type (n=5). The only variable being the change of coloringsubstance. At least one sample for each colored capsule is placed underthe light condition test described above and one identical controlsample is placed in dark conditions according to the above procedure(for an equivalent time period of 5 weeks).

C. ≢E₂₀₀₀ Measurement

For each of the samples the ΔE₂₀₀₀ (also referred to as CIEDE2000) ismeasured following ISO norm n° ISO/CIE 11664-6:2014 (CIE S 014-6/E:2013)with Color Eye XTH spectrocolorimeter from GretagMacBeth, associatedwith software Color iQC. Sphere instrument (Standard calibration withgreen, white and black tiles, illuminant D65-10, color equationsaccording to DE2000).

The results are shown in Tables 1 and 2.

TABLE 1 % wt ΔE₂₀₀₀ ΔE₂₀₀₀ Colorant coloring (light ) (dark) nameproduct* supplier Source 5 weeks 5 weeks Blue 1 WILD huito 16.85 0.63Yam 1 Kalsec Yam 9.64 0.27 vivid red 1 Kalsec beetroot 7.64 3.43turmeric 1 Kalsec curcuma 18.59 0.46 fruit max akaï 1 Hansen spirulina13.03 0.56 fruit max 1 Hansen carrot 21.28 2.36 vanilla Vegex Lutéin 1Hansen marigold 24.44 0.30 flower (lutein) vegetone 1 Hansen tomato31.15 32.33 rich red (lycopene) starfruit bright 1 Hansen carthame/ 6.620.16 WS (carthame) safflower Turmeric T 1 Hansen curcuma 22.96 0.07 PT8WS color fruit 1 Hansen algae N/A** N/A** yellow carotenoid 350 WSS pinkopaque 1 GNT sweet potato 7.44 0.20 shade blueberry 1 GNT blackcurrant11.56 1.19 red opaque Shade fruity 1 GNT grape 10.20 1.07 red clearopaque shade Mint 1 GNT green (mix of 12.83 0.60 green spirulina andsafflower @ 50:50 wt) *Tor all above tests a 1% wt of specified colorantwas added to the composition of Example 1, by weight of the totalcomposition (all other components kept equal). **non-homogenouscomposition resulted with unacceptable visual appearance.

TABLE 2 % wt ΔE₂₀₀₀ ΔE₂₀₀₀ Colorant coloring (light ) (dark) nameproduct* supplier source 5 weeks 5 weeks Lemon Yellow 2 GNT Carthame/6.19 0.30 transparent safflower Summer red 2 GNT radish/ 5.06 0.23transparent carrot cherry red 2 GNT purple 6.20 1.08 carrot yam 2 Kalsecyam 14.13 0.59 pink 2 GNT sweet 6.36 0.28 potato vivid red 2 Kalsecbeetroot 7.98 3.63 shade blue 2 GNT spirulina 14.44 0.53 Shade fruity 2GNT grape 9.97 1.29 red clear *For all above tests a 2% wt of specifiedcolorant was added to the composition of Example 1, by weight of thetotal composition (all other components kept equal).

As can be observed in the above table coloring concentrates from thefollowing sources are found to be unacceptable for hard capsules asdescribed herein: curcuma, carrot, lutein, tomato, curcuma, and algaecarotenoid. In particular, algae carotenoid concentrates exhibithomogeneity issues.

Enrichment Factor Concentration

The enrichment factor as used herein is calculated by first analyzingthe coloring substance (or colorant/concentrate) to identify the total %wt of each of carbohydrates, fibres, proteins, lipids and pigment, byweight of the total coloring substance; and repeating the same for thesource material used for obtaining the coloring substance.

For example; measuring the amount of proteins by common methods in theart like the Kjeldahl method, generally based on food “digestion” with astrong acid (sulphuric acid), releasing nitrogen, that is then titrated[acc. to § 64 LFGB, Kjeldahl (N×6.25)]; measuring lipids by commonmethods in the art [acc. to § 64 LFGB, Weilbull-Stoldt, and forsaturates DGF C VI 10a, 11d mod.; GC/FID] like NMR spectroscopy;measuring carbohydrates by common methods in the art [IC, HPLC] likealcoholic extraction (e.g. sample is dried, ground, defatted by solventextraction, then the residue is boiled with an alcoholic solution (e.g.ethanol, methanol, and mixtures) and filtrated. The filtrate isclarified by treatment with an ion-exchange resin, and then finally monoand oligo-saccharides are identified and quantified by chromatography(HPLC); and measuring fibers by common methods in the art likegravimetric [acc. to § 64 LFGB, enzymat.-gravimetric SOP M 1010 nach ASUL 00.00-18].

The below formula (Equation 1) is then used to calculate the enrichmentfactor.

$\begin{matrix}{{Fe} = \frac{{Cp} \div {Np}}{{Cs} \div {Ns}}} & {{Equation}1}\end{matrix}$

wherein,

Fe=the “enrichment factor”

Cp=the “pigment(s) content (wt %)” in the colorant sample

Cs=the “pigment(s) content (wt %)” in the source material

Np=the “nutritive constituents content (% wt)” in the colorant sample[i.e. sum % wt of total carbohydrates, fibres, proteins, and lipids insaid sample]

Ns=the “nutritive constituents content (% wt)” in the source material[i.e. sum % wt of total carbohydrates, fibres, proteins, and lipids insaid source material]

The below exemplifies how the enrichment factor is calculated for agiven coloring agent.

Carrot Carrot Carrot colorant A colorant B (% wt on a dry (% wt on a dry(% wt on a dry weight basis) weight basis) weight basis) Carbohydrates40 45 0 Fibres 10 5 0 Proteins 10 12 14 Lipids 2 5 20 Pigment 0.1 0.3 4

Carrot colorant A [carrot concentrate]:

${Fe} = {\frac{0.3 \div \left( {45 + 5 + 12 + 5} \right)}{0.1 \div \left( {40 + 10 + 10 + 2} \right)} \approx 3}$

Carrot colorant B [carrot extracted pigment]:

${Fe} = {\frac{4 \div \left( {14 + {20}} \right)}{0.1 \div \left( {40 + {10} + {10} + 2} \right)} \approx {73}}$

EXAMPLES Example 1 Aqueous Composition for the Manufacture ofHydroxypropyl Methyl Cellulose Hard Capsules with Hydrophilic ColoringFoodstuff Concentrate of Spirulina

A 5 kg composition of 18.8% HPMC type 2906 (methoxy content 28.7%,hydroxypropoxy content 5.4%) of 4.4 cPs viscosity at 2% concentration(w/w) was prepared as follows:

The HPMC powder is dispersed into hot water at 75° C. under stirring.Formation of foam is observed. After complete dispersion of the powder,the temperature is kept at 75° C. under very gentle stirring forde-foaming of the dispersion. Then the dispersion is cooled down to 10°C. under gentle stirring for obtaining dissolution of the HPMC. Afterkeeping the composition for more than 30 minutes at 10° C., thetemperature is increased to about 25° C. at which point the hydrophiliccoloring foodstuff concentrate of spirulina (1% w/w) [with Fe of about4.5] is then directly added to the HPMC aqueous composition, and adipping composition ready for use in capsule manufacturing is obtained.

A dip-molding process as described herein is then followed forgenerating hard capsules by dipping pre-heated mold pins (at atemperature of about 60° C.) into the dipping composition.

The HPMC composition gelling temperature is determined by viscositymeasurement by progressively heating the composition. The gellingtemperature is about 34° C.

Example 2 Aqueous Composition for the Manufacture of HydroxypropylMethyl Cellulose Hard Capsules with Hydrophilic Coloring FoodstuffConcentrate of Purple Carrot

Example 1 is repeated but this time replacing the 1% w/w of spirulinawith purple carrot concentrate [with Fe of about 3].

Example 3 Aqueous Composition for the Manufacture of HydroxypropylMethyl Cellulose Hard Capsules with Hydrophilic Coloring FoodstuffConcentrate of Safflower

Example 1 is repeated but this time replacing the 1% w/w of spirulinawith safflower concentrate [with Fe of about 5].

Example 4 Aqueous Composition for the Manufacture of HydroxypropylMethyl Cellulose Hard Capsules with Hydrophilic Coloring FoodstuffConcentrate of Sweet Potato

Example 1 is repeated but this time replacing the 1% w/w of spirulinawith sweet potato concentrate [with Fe of about 4].

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “40 mm” is intended to mean“about 40 mm” (i.e. every value in a practical range close to 40 mm).

1. A two-piece hard capsule shell comprising: a film forming capsulebase material; and a colorant, wherein the colorant consists of ahydrophilic coloring foodstuff concentrate having an enrichment factorof less than
 6. 2. The two-piece hard capsule shell according to claim 1wherein the film forming capsule base material comprises one or morecelluloses, gelatin, pullulan, or any combination thereof.
 3. Thetwo-piece hard capsule shell according to claim 1 wherein the filmforming capsule base material comprises one or more celluloses.
 4. Thetwo-piece hard capsule shell according to claim 1 wherein the filmforming capsule base material comprises hydroxypropyl methyl cellulose(HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS),hydroxypropyl methyl cellulose phthalate (HPMCP), or methylcellulose(MC).
 5. The two-piece hard capsule shell according to claim 1 whereinthe film forming capsule base material comprises HPMC.
 6. The two-piecehard capsule shell according to claim 1 wherein the hydrophilic coloringfoodstuff concentrate is present in an amount from about 0.001 wt % toabout 5 wt % based on the empty hard capsule weight.
 7. The two-piecehard capsule shell according to claim 1, further comprising aplasticizer, an antibacterial agent, a flavouring agent, or anycombination thereof.
 8. A dip-molding process for making a two-piecehard capsule shell comprising: providing an aqueous compositioncomprising a film forming capsule base material; mixing a colorant withthe aqueous composition to provide a dipping composition, the colorantconsisting of a hydrophilic coloring foodstuff concentrate having anenrichment factor of less than 6; dipping one or more mold pins in thedipping composition; extracting the one or more mold pins from thedipping composition such that a film is formed over the pins; and dryingthe film to provide a two-piece hard capsule shell.
 9. The dip-moldingprocess according to claim 8, wherein the aqueous composition ismaintained at a temperature of from 25° C. to 45° C.
 10. The dip-moldingprocess according to claim 8, wherein the aqueous composition and thedipping composition have a pH of less than
 6. 11. The dip-moldingprocess according to claim 8, wherein the mold pins are pre-heated to atemperature that is greater than a gelation temperature of the dippingcomposition prior to dipping the one or more mold pins in the dippingcomposition.
 12. The dip-molding process according to claim 11, whereinthe dipping composition is maintained at a temperature of 1° C. to 10°C. below the gelation temperature of the dipping composition whendipping the one or more mold pins in the dipping composition.
 13. Thedip-molding process according to claim 8, wherein drying is performed ata temperature of less than 65° C.
 14. The dip-molding process accordingto claim 8, wherein the film forming capsule base material comprises oneor more celluloses, gelatin, pullulan, or any combination thereof. 15.The dip-molding process according to claim 8, wherein the film formingcapsule base material comprises hydroxypropyl methylcellulose (HPMC).16. The dip-molding process according to claim 15, wherein: (i) the HPMCis a HPMC having a viscosity of 4.0 to 5.0 cPs as a 2% w/w solution inwater at 20° C.; or (ii) a concentration of the HPMC in the aqueouscomposition provides a viscosity of 1000 to 3000 cPs measured at atemperature of from 10° C. to 1° C. below a gelling temperature of theaqueous composition; or (iii) both (i) and (ii).
 17. The dip-moldingprocess according to claim 8, wherein the two-piece hard capsule shellcomprises the film forming capsule base material in an amount from about80 wt % to about 99 wt %.
 18. The dip-molding process according to claim8, wherein the two-piece hard capsule shell comprises the colorant in anamount from about 0.001 wt % to about 5 wt %.
 19. The dip-moldingprocess according to claim 8, wherein the two-piece hard capsule shellcomprises water in an amount from about 1 wt % to about 8 wt %.
 20. Thedip-molding process according to claim 8, wherein the hydrophiliccoloring foodstuff concentrate is a concentrate of purple carrot,pumpkin, yam, radish, sweet potato, beetroot, elderberry, blackcurrant,grape, apple, huito, safflower, carthamus, hibiscus, tropaeolum,spirulina, chlorella, or any mixture thereof.